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Overall Survival Benefit with VELCADE® based Therapy in Previously Untreated Multiple Myeloma Patients Maintained after Five Year Follow-Up

−VELCADE added to a standard frontline therapy demonstrates 43.9 percent overall survival improvement in landmark phase III VISTA trial −
− Additional study shows VELCADE based maintenance nearly doubles complete response rate following VELCADE based induction −

SAN DIEGO, Calif., December 12, 2011 - Millennium: The Takeda Oncology Company with its parent company Takeda Pharmaceutical Company Limited (TSE:4502) today reported results from the final five-year follow-up analysis of the international, multicenter, Phase III VISTA1 trial. The analysis assessed overall survival (OS) after treatment with VELCADE (bortezomib) in combination with melphalan and prednisone (VcMP) versus melphalan and prednisone (MP) alone, in patients with previously untreated multiple myeloma (MM) at a median follow-up of 60.1 months. The data were presented by Professor Jesús F. San Miguel, M.D., Ph.D., Hospital Clìnico Universitario de Salamanca, Salamanca, Spain, during an oral session at the 53rd annual meeting of the American Society of Hematology (ASH), held December 10-13, 2011 in San Diego, California. These long-term OS data were also the basis of the recent FDA-approved label update for VELCADE.

“This VELCADE-based therapy resulted in an impressive 13.3-month increase in the median overall survival after five years of follow-up,” said San Miguel. “These data confirm that starting previously untreated multiple myeloma patients with the VELCADE based combination (VcMP) provided a significant survival advantage over MP, a recognized standard of care, that could not be regained despite the substantial use of novel agent based salvage therapies including VELCADE.”

The VISTA trial was conducted in 682 previously untreated MM patients ineligible for high-dose therapy, and compared VcMP versus MP treatment alone. The primary endpoint of the study was time-to-disease progression, and secondary end points for the study were: OS, progression free survival (PFS), response rates and safety. After a median follow-up of 60.1 months, median OS was 56.4 versus 43.1 months for patients randomized to VcMP and MP, respectively - a significant survival advantage of 13.3 months for the VcMP arm (p=0.0004). An exploratory analysis of the incidence rate of secondary primary malignancies (SPM) reported an exposure-adjusted incidence rate of 1.66 SPM per 100-patient-years for VcMP, and 1.30 SPM for MP alone.

“Elderly patients with multiple myeloma strive for upfront therapy that will extend their lives,” said Karen Ferrante, M.D., Chief Medical Officer, Millennium. “Today's VELCADE data confirmed the sustained clinical benefits, including overall survival and complete response, that VELCADE provided in patients with previously untreated MM.”

Continued Overall Survival Benefit After 5 Years' Follow-Up with Bortezomib-Melphalan-Prednisone (VcMP) Versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial (Abstract #476)

The updated results showed:

  • After a median follow-up of 60.1 months, median OS was 56.4 months in the VcMP arm compared to 43.1 months in the MP arm (HR 0.695, p=0.0004), reflecting a 13.3-month OS advantage
  • Among patients who received subsequent therapies, OS was significantly longer in patients who received VcMP upfront compared to those who received MP (median 55.7 vs. 46.4 months; HR 0.745, p=0.0162)
  • Time to next treatment (median 27.0 vs. 19.2 months; HR 0.557, p<0.0001) and treatment-free interval (median 16.6 vs. 8.3 months, HR 0.573, p<0.0001) were longer with VcMP versus MP
  • The exposure-adjusted incidence rate of 1.66 SPM per 100-patient-years for VcMP, and 1.30 SPM for MP alone

Patients were randomized (1:1) to receive nine 6-week cycles of VcMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1 - 4, days 1, 8, 22, and 29, cycles 5 - 9; melphalan 9 mg/m2 days 1 - 4, prednisone 60 mg/m2, days 1 - 4, all cycles) or MP (N=338) alone. Patients were followed at least every 12 weeks for survival and subsequent therapy use. Data on SPM were collected by surveying all study sites to capture information for 655 (96 percent) patients.

Maintenance therapy with bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP) after induction with bortezomib, melphalan and prednisone (VcMP) or bortezomib, thalidomide and prednisone (VTP) in elderly untreated myeloma patients included in the GEM2005MAS65 Spanish randomized trial. (Abstract #477)

This Phase III trial in 260 elderly patients, with a median age of 73 years, was conducted by the Spanish Myeloma Group PETHEMA/GEM. The patients remained on maintenance therapy for up to three years. One third of the patients were over the age of 75. The updated results, presented by María-Victoria Mateos, M.D., Hospital Universitario de Salamanca, Salamanca, Spainshowed:

  • Maintenance therapy with VT or VP resulted in an increase in immunofixation-negative complete response (CR) rates from 24 percent after induction to 42 percent, after a median of 20 months of maintenance therapy
  • At a median follow-up of 46 months, median PFS was 39 months for patients receiving VT maintenance and 32 months for patients receiving VP maintenance (p=0.1)
  • Median OS for the VP arm was 60 months; median OS for the VT arm has not yet been reached at a median follow-up of 46 months since first randomization
  • Most common grade ≥3 adverse events in the maintenance phase were;
    • VT: Peripheral neuropathy (9 percent), GI symptoms (4 percent), asthenia and cardiac events (each 2 percent), neutropenia (1 percent)
    • VP: Peripheral neuropathy (3 percent), GI symptoms (0 percent), asthenia (0 percent), cardiac events (1 percent), neutropenia (0 percent)

Patients were randomized to receive six cycles of VMP or VTP as induction therapy followed by randomization to maintenance. Maintenance therapy included VELCADE 1.3 mg/m2 on day 1, 4, 8, 11 every three months for both arms, plus either thalidomide 50 mg daily for VT or prednisone 50 mg every other day for VP for up to three years.

About VELCADE
VELCADE is co-developed by Millennium and Janssen Pharmaceutical Companies of Johnson & Johnson. Millennium is responsible for commercialization of VELCADE in the U.S., Janssen Pharmaceutical Companies of Johnson & Johnson are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote VELCADE in Japan. VELCADE is approved in more than 90 countries and has been used to treat more than 300,000 patients worldwide.

Important Safety Information
VELCADE® (bortezomib) is approved for the treatment of patients with multiple myeloma. VELCADE is also approved for the treatment of patients with mantle cell lymphoma who have already received at least one prior treatment.

Patients should not receive VELCADE if they are allergic to bortezomib, boron or mannitol. Women should be advised not to take VELCADE while pregnant or breast-feeding. Patients with diabetes may require close monitoring and adjustment of their medication.

VELCADE can cause serious side effects, including:

  • Lowering the levels of blood cells, which could result in a higher risk for infections or bleeding.
  • Nausea, vomiting, diarrhea and constipation.
  • Nerve problems, which can be severe including muscle weakness, tingling, burning, pain, or loss of feeling in the hands and feet.
  • A drop in blood pressure resulting in dizziness, light headedness or fainting.
  • Heart rhythm problems and heart failure including worsening of existing conditions. Symptoms may include chest pressure or pain, palpitations, swelling of the ankles or feet, or shortness of breath.
  • Lung disorders, some of which have been fatal. Symptoms include cough, shortness of breath, wheezing or difficulty breathing.
  • Liver failure including a yellow discoloration of the eyes and skin.
  • Tumor Lysis Syndrome and Reversible Posterior Leukoencephalopathy Syndrome have been reported.

Common side effects seen in patients receiving VELCADE include: fever, decreased appetite, fatigue, insomnia and headache.

Additional information and full prescribing information is available at www.VELCADE.com.
Please see the full prescribing information for VELCADE including warnings and precautions.

For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-866-VELCADE (1-866-835-2233).

Editor's Note: This press release is also available under the Media section of the Company's website at: www.millennium.com/InTheNews.aspx.

About Millennium
Millennium: The Takeda Oncology Company, a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a first-in-class proteasome inhibitor, and has a robust clinical development pipeline of product candidates. Millennium Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical Company Ltd. in May, 2008. The Company's research, development and commercialization activities are focused in oncology. Additional information about Millennium is available through its website, www.millennium.com.

About Takeda
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, www.takeda.com.

Contacts:
Millennium
Manisha Pai
+1-617-551-7877
Manisha.pai@mpi.com

David Albaugh
+1-617-444-4456
david.albaugh@mpi.com

Takeda Pharmaceutical Company Limited
Corporate Communications Dept. (PR/IR)
Tel: +81-3-3278-2037

1(VELCADE as Initial Standard Therapy in Multiple Myeloma)